SROJECT SUMMARY. Alcohol dependence is a major public health problem for which existing treatments have limited efficacy. During the previous funding period, our double-blind, placebo-controlled study showed significant effects for gabapentin relative to placebo on drinking, sleep, and mood in recently abstinent alcohol dependent outpatients. We propose to build on these findings using a 3-arm design to study the efficacy of pregabalin (Lyrica) and duloxetine (Cymbalta) relative to placebo for reducing drinking relapse, pregabalin is a newer anticonvulsant/analgesic drug that, like gabapentin, appears to act indirectly on both GABA and glutamate systems to reduce CNS hyperexcitability characteristic of early abstinence from alcohol, and may reduce pathological drinking by stabilizing physiological dysregulation underlying disturbances in mood and sleep, both common precipitants of relapse. Conversely, duloxetine (Cymbalta) is a serotonin/norepinephrine reuptake inhibitor (SNRI) antidepressant/analgesic that is hypothesized to act as an indirect serotonin and norepinephrine agonist, and to act on impulsivity circuits including frontal cortex, NA and VTA, which may decrease drinking via regulation of reward-driven impulsivity. A 10-week, double- blind, placebo-controlled, parallel group study will be conducted in 150 outpatients with alcohol dependence, with random assignment to pregabalin 300mg/d, duloxetine 40mg/d, or placebo in conjunction with manual- guided behavioral counseling. The specific aims are: 1.) To evaluate the efficacy and safety of pregabalin as a treatment for alcohol dependence relative to double-blind placebo; 2.) To evaluate the efficacy and safety of duloxetine as a treatment for alcohol dependence relative to double-blind placebo; and 3.) To test both pregabalin and duloxetine in our cue reactivity lab model to assess the predictive validity of the lab model for determining clinical efficacy. It is hypothesized that treatments targeting different neurobiological substrates underlying dependence will be effective on different phenotypes of the alcohol dependence syndrome. RELEVANCE. Results will provide key information about the efficacy and safety of pregabalin and duloxetine for relapse prevention during early abstinence in outpatients with alcohol dependence, and will provide a heuristic framework for making predictions regarding the interaction of phenotype with different neuropharmacological targets in the treatment of alcohol dependence.